Dendritic cells (DCs) have recently emerged as pivotal players in the development and maintenance of CNS autoimmunity and inflammation. During the previous funding cycle, it was discovered that DC mediated T cell amplification pathways play a critical role in T cell recruitment and function in the CNS. A second major finding was that DCs migrate from the brain to secondary lymphoid organs during CNS inflammation, and this process was critical for the induction and regulation of antigen-specific T cell responses. These discoveries led to novel hypotheses about the role of DCs in the initiation of CNS directed inflammatory responses. The studies proposed in the current application will test the overall hypothesis that DCs are critical for the initiation, regulation, and maintenance of antigen-specific T cell mediated autoimmune responses in the CNS. Specifically, studies proposed in Aim 1 will test the hypothesis that phenotypically and functionally distinct populations of DCs are dynamically recruited to the CNS during chronic progressive experimental autoimmune encephalomyelitis (EAE). These studies will employ a novel method of DC-tracking using magnetic/fluorescent nanobeads to measure the kinetics of DC accumulation in the CNS at various time points following EAE induction. In addition, the role of brain DCs in regulating cellular infiltration into the CNS and the onset of clinical symptoms during CNS autoimmune disease will be determined (Aim 2). Finally, studies proposed in Aim 3 will determine whether CNS DCs sample multiple antigens expressed in oligodendrocytes and amplify antigen-specific immune responses during the initiation and progression of neuro-autoimmune disease. The successful completion of these studies will further define the role of DCs in CNS autoimmune disease and may lead to novel therapeutic strategies for the treatment of inflammatory diseases in the nervous system. PUBLIC HEALTH RELEVANCE: Neuroinflammation in autoimmune and infectious diseases of the central nervous system (CNS) is a result of the activation of the immune system. Recently, CNS dendritic cells (DCs) emerged as pivotal players to regulate this activation process. This present application is designed to understand the pathogenesis of autoimmunity in the CNS and the role of DCs in the initiation and maintenance of CNS inflammatory responses. The outcome of these studies will lead to an improved understanding of the mechanisms of antigen-specific T cell recruitment into the CNS and may provide the foundation for new therapeutic strategies for controlling CNS inflammatory diseases.